Neurobiological and Behavioral Effects of Cytokine Antagonism in Major Depression

描述(由申请人提供)：越来越多的数据表明，先天免疫炎症反应的激活可能有助于重度抑郁症的发展。医学上健康的抑郁症患者表现出包括先天免疫系统细胞因子在内的血浆炎症介质浓度增加，给动物和人类注射先天免疫细胞因子会导致与严重抑郁症重叠的行为改变。此外，先天免疫反应中的细胞因子与抑郁症病理生理学中涉及的途径相互作用。越来越多的人对通过免疫系统治疗抑郁症的兴趣集中在肿瘤坏死因子-α上。已发现重度抑郁症患者血浆中的肿瘤坏死因子-α浓度升高，并且已知的是，肿瘤坏死因子-α激活了改变HPA轴功能、单胺代谢和突触可塑性的信号通路，所有这些都是与重度抑郁症的发生发展相关的病理生理学领域。此外，携带肿瘤坏死因子-α受体基因敲除的实验动物表现出抗抑郁药样的表型，而传统抗抑郁药物(即单胺再摄取抑制剂)的疗效已被证明部分与对肿瘤坏死因子的影响有关。最后，拮抗肿瘤坏死因子-α活性已被证明可以改善自身免疫性疾病患者的抑郁症状。这项拟议工作的长期目标是使用一种肿瘤坏死因子-α拮抗剂来测试抑郁症的细胞因子假说。在目前的项目中，我们计划测量抑郁症患者对单次注射肿瘤坏死因子-α拮抗剂英夫利昔单抗的行为反应。考虑到肿瘤坏死因子-α拮抗的潜在健康风险，这项拟议的研究将专注于患有难治性抑郁症(TRD)且有先天免疫反应激活证据的健康内科患者。TRD是一种常见的重大公共卫生问题，在发病率和死亡率方面都会造成令人衰弱的后果。有趣的是，与治疗敏感的患者相比，TRD患者似乎更有可能表现出天然免疫系统的激活。我们假设，1)英夫利昔单抗输注将减少TRD患者的抑郁症状和增加炎症标志物，以及2)抑郁症的减少将与英夫利昔单抗诱导的肿瘤坏死因子-α活性的降低和先天免疫炎症反应的其他下游因素相关。为了验证这些假设，60名不服用抗抑郁药的TRD受试者将以双盲方式随机分为英夫利昔单抗和生理盐水两组。受试者将在基线以及注射英夫利昔单抗后的第1、2、4、6和8周接受定期的神经行为、免疫学和安全性评估。这项拟议的转化性研究将为肿瘤坏死因子-α在抑郁症中的作用提供新的见解，并将有助于确定预测或监测抗肿瘤坏死因子-α治疗成功的潜在生物标志物。重度抑郁症是导致全球总体健康负担的第四大原因。高达30%的抑郁症患者对目前可用的治疗没有反应，这是造成这种疾病的人力和经济成本的主要因素。本申请建议评估阻断细胞因子肿瘤坏死因子(TNF)-α作为治疗难治性抑郁症干预的新治疗策略，基于数据表明，过度活跃的免疫系统反应，包括过度释放细胞因子，如肿瘤坏死因子-α，可能有助于该疾病的病理生理学。

DESCRIPTION (provided by applicant): Accumulating data suggest that activation of the innate immune inflammatory response may contribute to the development of major depression. Medically healthy patients with depression exhibit increased plasma concentrations of inflammatory mediators including cytokines of the innate immune system, and administration of innate immune cytokines to animals and humans induces behavioral alterations that overlap with major depression. In addition, cytokines of the innate immune response interact with pathways implicated in the pathophysiology of depression. Increasing interest in targeting the immune system for the treatment of depression has focused on tumor necrosis factor (TNF)-alpha. Plasma concentrations of TNF-alpha have been found to be elevated in patients with major depression, and TNF-alpha is known to activate signaling pathways that alter HPA axis function, monoamine metabolism and synaptic plasticity; all of which are pathophysiologic domains relevant to the development of major depression. Furthermore, laboratory animals with the TNF-alpha receptor gene knocked out exhibit an antidepressant-like phenotype, and the efficacy of traditional antidepressants (i.e. monoamine reuptake inhibitors) has been shown to be related in part to effects on TNF. Finally, antagonism of TNF-alpha activity has been shown to improve depressive symptoms in patients with autoimmune disorders. The long-term goal of the proposed work is to test the cytokine hypothesis of depression using a TNF-alpha antagonist. In the current project, we plan to measure the behavioral response of depressed patients to a single infusion of the TNF-alpha antagonist, infliximab. Given the potential health risks of TNF-alpha antagonism, the proposed study will focus on medically healthy patients with both treatment resistant depression (TRD) and evidence of activation of the innate immune response. TRD is a common and significant public health concern with debilitating consequences in terms of both morbidity and mortality. Interestingly, patients with TRD also appear to be more likely than treatment responsive patients to demonstrate innate immune system activation. We hypothesize that 1) infliximab infusion will decrease depressive symptoms in patients with TRD and increased markers of inflammation and 2) that decreases in depression will correlate with infliximab-induced decreases in TNF-alpha activity and other downstream elements of the innate immune inflammatory response. To test these hypotheses, sixty antidepressant-free subjects with TRD will be randomized in double-blind fashion to a single infusion of infliximab versus saline. Subjects will undergo regular neurobehavioral, immunologic and safety assessments at baseline and at weeks 1, 2, 4, 6 and 8 following infliximab infusion. The proposed translational research will provide novel insights into the role of TNF-alpha in depression and will help define potential biomarkers that predict or monitor success of anti-TNF-alpha therapy.Major depression is the fourth leading cause of overall health burden in the world. Non-response to currently available therapies in up to 30% of depressed patients is a primary contributor to the human and economic cost of the disease. This application proposes to evaluate the novel therapeutic strategy of blocking the cytokine tumor necrosis factor (TNF)-alpha as an intervention for treatment-resistant depression, based on data suggesting that overactive immune system responses, including excessive release of cytokines like TNF- alpha, may contribute to the pathophysiology of the disorder.